Heterocyclic compounds as aldose reductase inhibitors

ABSTRACT

Certain spirocyclic heterocyclic compounds, and their pharmaceutically-acceptable salts, are inhibitors of the aldose reductase enzyme, and so are useful for the control of diabetic complications. Exemplary compounds include compounds of the formula ##STR1## wherein Y is ##STR2## X is --O-- or ##STR3## R 1  and R 2  are each independently H, alkyl C 1  -C 6 ,aryl or arylalkyl (C 1  -C 6 ); 
     W 1  and W 2  are each independently hydrogen, halogen or nitro; and 
     the pharmaceutically acceptable base addition salts thereof.

TECHNICAL FIELD

The field of art to which this invention relates is heterocycliccompounds which are useful in the field of medicinal chemistry. Moreparticularly the invention relates to spirocyclic heterocylic compoundswhich are aldose reductase inhibitors useful for the control of diabeticcomplications such as neuropathy, nephropathy, retinopathy andcataractogenesis.

BACKGROUND ART

In the past, various attempts have been made by numerous investigatorsin the field of organic medicinal chemistry to obtain new and betteroral antidiabetic agents. Many of these efforts have involved thesyntheses and testing of various new and unavailable organic compounds,particularly in the area of the sulfonylureas, in an endeavor todetermine their ability to lower blood sugar (i.e., glucose) levels to asubstantially high degree when given by the oral route ofadministration. The effect of other organic compounds in preventing orarresting certain chronic complications of diabetes, such as diabeticcataracts, neuropathy and retinopathy, etc. has also been studied. Forexample, K. Sestanj et al. in U.S. Pat. No. 3,821,383 discloses thatcertain aldose reductase inhibitors like1,3-dioxo-1H-benz[d,e]isoquinoline-2(3H)-acetic acid and some closelyrelated derivatives thereof are useful for these purposes, even thoughthese particular compounds are not known to be hypoglycemic in nature.

In addition, for example, commonly assigned U.S. Pat. No. 4,130,714entitled "Hydantoin Therapeutic Agents" the disclosure of which ishereby incorporated by reference discloses dextrorotatoryspiro-hydantoin compounds such asd-6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione andd-6'-fluoro-spiroimidazolidine-4,4'-thiochroman-2,5-dione.

Non-hydantoin compounds previously reported to inhibit aldose reductaseinclude 1H-benz[d,e]isoquinoline-1,3(2H)-dione-2-acetic acidderivatives, Sestanj et al., U.S. Pat. No. 3,821,383; halogensubstituted chroman-4-carboxylic and chroman-4-acetic acids, Belletire,U.S. Pat. No. 4,210,663; spiro-[chroman-4,5'-oxazolidin]-2',3'-diones,Schnur, U.S. Pat. No. 4,200,642; and variously substitutedphthalazin-1(2H)-on-4-acetic acids, Larson et al., published EuropeanPatent Application No. 222,576.

These aldose reductase inhibitors all function by inhibiting theactivity of the enzyme aldose reductase, which is primarily responsiblefor regulating the reduction of aldoses (like glucose and galactose) tothe corresponding polyols (such as sorbitol and galactitol) in the humanbody. In this way, unwanted accumulations of galactitol in the lens ofgalactosemic subjects, and of sorbitol in the lens, peripheral nervouscord and kidney of various diabetic subjects, are thereby reduced orprevented. As a result, these compounds are of value as aldose reductaseinhibitors for controlling chronic diabetic complications, including butnot restricted to those of an ocular nature, since it is known that thepresence of polyols in an eye lens invariably leads to cataractformation and a loss of lens clarity.

Although compounds such as the hydantoins have proven useful for thetreatment of diabetic complications there is a continuing search in thisfield of art for different, more effective inhibitors for the treatmentof diabetic complications.

SUMMARY OF THE INVENTION

This invention is directed to spirocyclic heterocyclic compounds thatare useful as aldose reductase inhibitors. The compounds of thisinvention have the formula ##STR4## wherein Y is ##STR5## X is --O-- or##STR6## R₁ and R₂ are each independently H, alkyl C₁ -C₆, aryl orarylalkyl C₁ -C₆);

W₁ and W₂ are each independently hydrogen, halogen or nitro; and

the pharmaceutically acceptable cationic salts thereof.

Particularly preferred are compounds of formula (I) where X is ##STR7##Preferred within this group are compounds where W₁ is hydrogen, W₂ isfluorine, Y is ##STR8## and R₁ and R₂ are each independently H oralkyl(C₁ -C₆). Preferred within this group is a compound where R₁ ishydrogen, R₂ is methyl, and fluorine is in position 6.

A second preferred group of compounds of formula (I) are those where Xis --O--. Preferred within this group are compounds where Y is ##STR9##W₁ and W₂ are each independently hydrogen or halogen, and R₁ and R₂ areeach independently H or alkyl(C₁ -C₆) Preferred within this group arecompounds where R₁ is hydrogen or methyl, R₂ is hydrogen or methyl, W₁and W₂ are chlorine in position 6 and 7 respectively or W₁ is hydrogenand W₂ is fluorine in position 6.

Another preferred group of compounds of formula (I) where X is --O-- arecompounds where Y is ##STR10## W₁ and W₂ are each independently hydrogenor halogen, R₁ is hydrogen and R₂ is hydrogen, alkyl(C₁ -C₆) orarylalkyl(C₁ -C₆) Preferred within this group are compounds where R₂ ishydrogen, methyl, n-propyl or --CH₂ CH₂ C₆ H₅ and W₁ and W₂ are chlorinein position 6 and 7 respectively or W₁ is hydrogen and W₂ is fluorine inposition 6.

Another preferred group of compounds of formula (I) where X is -0- arecompounds where Y is ##STR11## W₁ and W₂ are each independently hydrogenor halogen, R₁ is hydrogen, and R₂ is H or alkyl (C₁ -C₆). Preferredwithin this group are compounds wherein R₂ is hydrogen or methyl, W₁ andW₂ are each chlorine in position 6 and 7 respectively or W₁ is hydrogenand W₂ is fluorine in position 6.

Yet another preferred group of compounds of formula I where X is --O--are compounds where Y is ##STR12## W₁ and W₂ are each independentlyhydrogen or halogen and R₁ and R₂ are hydrogen.

Yet another preferred group of compounds of formula I where X is --O--are compounds where Y is ##STR13## W₁ and W₂ are each independentlyhydrogen or halogen and R₁ and R₂ are hydrogen.

The present invention is also directed to pharmaceutical compositionsfor the control of chronic diabetic complications in mammals whichcomprise a compound of the formula (I) in a pharmaceutically acceptablecarrier; and to a method of controlling chronic diabetic complicationswhich comprises administering to a mammal suffering from chronicdiabetes a chronic diabetic complication controlling amount of acompound of the formula (I).

Other features and advantages will be apparent from the specificationand claims.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention may be made using the appropriate(appropriately substituted to achieve the desired W₁, W₂, X and R₂functionalities) compound of formula II illustrated empirically below,as starting material: ##STR14## where W₁, W₂ are hydrogen, nitro orhalogen; X is oxygen or carbonyl; R₂ is H, alkyl (C₁ -C₆), aryl orarylalkyl (C₁ -C₆) and R₃ is alkyl (C₁ -C₆) or arylalkyl. Aryl as usedherein is defined as including for example, phenyl and phenylsubstituted with chlorine, methoxy, etc. Halogen as used herein isdefined as chlorine, bromine, fluorine or iodine.

The above described ester compounds of formula II where X is --O-- maybe produced from the corresponding 2,3-dihydro-4H-benzopyran-4-one(appropriately substituted to achieve the desired W₁, W₂ and R₂functionalities) according to Example 1. The desired2,3-dihydro-4H-benzopyran-4-one starting compound may be producedaccording to the following reaction sequence and as exemplified inExample 11. Phenol (appropriately substituted to achieve the desired W₁,W₂ substitutents) is heated to reflux with an acrylonitrile(appropriately substituted to achieve the desired R₂ substituent) andTriton B (N-benzyltrimethylammonium hydroxide) for over 35 hours toproduce the desired phenoxy propionitrile. The phenoxy propionitrile ishydrolyzed under acidic conditions to the corresponding carboxylic acid.The carboxylic acid is cyclized to the ketone by acid treatment at 50°C. for 15-45 minutes followed by quenching with water. (J. Med. Chem.,28, 1716 (1985)). The phenol and acrylonitrile starting compounds can beeasily synthesized by those skilled in the art starting from commonchemical reagents using conventional methods of organic synthesis.

When X is carbonyl, the above described ester compounds of formula IImay be produced according to the following sequence. A phenylacetateester (appropriately substituted to achieve the desired W₁ and W₂functionality) is reacted with a methacrylate (appropriately substitutedto achieve the desired R₂ functionality) under basic catalysis, forexample, tertbutoxide in N,N-dimethylformamide. The resulting diester issaponified to the corresponding diacid which is then cyclized underacidic conditions to yield the ketone carboxylic acid. The carboxylicacid function is then esterified under acidic conditions to yield thedesired tetralone-4-carboxylic acid ester.

In general, for the production of compounds of formula I in which Y is##STR15## the above described ester compounds of formula II undergo analdol reaction (utilizing the appropriate aldehyde to achieve thedesired R₁ functionality in Formula I) to yield the desired hydroxyester (III) as described empirically below: ##STR16## Preferably theester is reacted with a strong base such as a sterically hindered amideion (e.g., lithium diisopropylamide) at temperatures below about -66° C.to achieve anion formation. The resulting intermediate is reacted withthe desired aldehyde at temperatures below about -66° C. Typically anaprotic solvent such as THF is used.

The beta-hydroxy ester (III) thus obtained is hydrolyzed to thecorresponding hydroxy acid (IV) as described empirically below:##STR17## Preferably the ester is saponified to the carboxylic acid. Itis especially preferred that the ester is heated with a base such assodium hydroxide in aqueous methanol to effect hydrolysis. Thebeta-hydroxy acid is isolated after acidification to pH 3-6.

Alternatively, when R₃ is benzyl, the beta-hydroxy acid is obtained byhydrogenolysis. This reaction sequence reduces an undesired retro aldolreaction that can occur in the above described saponification sequencebecause it eliminates the need for basic reaction conditions.

The hydroxy acid (IV) (from either of the above reaction sequences) isconverted to the corresponding hydroxamic acid (V) by coupling with anO-substituted hydroxylamine such as O-benzylhydroxylamine in thepresence of a carbodiimide. This yields the O-substituted hydroxamicacid as described empirically below: ##STR18## where R is an alkyl groupsuch as benzyl or methyl. Preferably the hydroxyacid is reacted withO-benzylhydroxylamine and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidein a protic solvent system such as aqueous DMF at a pH of about 3.5 toabout 5.5 because within that pH range coupling is facilitated.

The O-substituted beta-hydroxyhydroxamic acid (V) thus obtained is thenacylated to yield the corresponding sulfonate ester (VI) as describedempirically below: ##STR19## where Q is CH₃ SO₃ --.

Preferably the sulfonate ester of the alcohol is made by reaction with asulfonyl chloride in pyridine at temperatures below about roomtemperature.

The sulfonate ester (VI) is then cyclized (i.e., lactamized) to thecorresponding N-alkoxy beta-lactam (VII) as described empirically below:##STR20## Preferably the sulfonate ester is heated at reflux with a basesuch as potassium carbonate to eliminate methanesulfonic acid and yieldthe N-alkoxy beta-lactam.

When R equals phenylmethyl the N-benzylozy beta-lactam (VIII) undergoeshydrogenolysis as described empirically below to yield the correspondingdesired end product, the N-hydroxy beta-lactam (VIII): ##STR21##Preferably the benzyl ether and a noble metal catalyst are stirred in ahydrogen atmosphere at ambient temperatures in protic solvents such asalcohol at elevated pressures such as 5-50 psi.

In general for the production of compounds of formula I in which Y is##STR22## the above described N-hydroxy beta-lactam (VIII) undergoes anacid catalyzed rearrangement as described empirically below to yield thecorresponding isoxazolidin-5-one (IX): ##STR23## Preferably a solutionof the N-hydroxy lactam in a protic solvent containing a catalyticamount of acid is stirred at ambient temperature to affect therearrangement.

For the production of compounds of formula I in which Y is ##STR24##(the cyclopentanedione functionality) the following reaction sequence istypically used. The ester (II) (appropriately substituted to achieve thedesired W₁, W₂, X, and R₂ functionalities) is alkylated using the bromoester (appropriately substituted to achieve the desired R₁ substituent)to yield the desired dicarboxylic acid ester (X) as describedempirically below: ##STR25## Preferably the methyl ester is reacted witha base such as sodium hydride at ambient conditions to affect anionformation and then the appropriate methyl ester halide is added.

The diester (X) is then subjected to Dieckmann cyclization conditions toyield the corresponding beta-ketoester (XI) as described empiricallybelow: ##STR26## Preferably, the diester is reacted with a base such asNaH, at ambient conditions in solvents such as DMF, THF, or dioxane andthen acidified to a pH about 4-6 to facilitate product isolation.

The beta-keto ester (XI) undergoes a hydrolysis and decarboxylation asdescribed empirically below to yield the corresponding cyclopentanone(XII): ##STR27## Preferably the beta-keto ester is refluxed with acid.

The cyclopentanone (XII) undergoes an oximation as described empiricallybelow to yield the cyclopentanone oxime (XIII): ##STR28## Preferably thecyclopentanone is reacted at temperatures -30° C. to about 0° C. with analkyl nitrate and a base in an aprotic solvent.

The cyclopentanone oxime (XIII) undergoes an acid catalyzed hydrolysisas described empirically below to yield the desired end productcyclopentanedione (XIV): ##STR29## Preferably, the cyclopentanone oximeis refluxed with aqueous acid.

In general for the production of compounds of formula I in which Y is##STR30## the following reaction sequence is typically utilized. Theappropriately substituted 2,3-dihydro-4H)-benzopyran-4-carboxylate ester(II) (i.e., substituted to achieve the desired W₁, W₂, X, and R₂functionality) undergoes an allylation to yield the desired alkylatedester (XV) as described empirically below: ##STR31##

Preferably the carboxylate ester is dissolved in a polar aprotic solventsuch as anhydrous N,N-dimethylformamide and added to a base such assodium hydride under an inert gas. The reaction mixture is typicallycooled to avoid an uncontrolled exotherm and the appropriate allylichalide is added to achieve the desired R₁ substituent.

The allylic substituent is then oxidized to an aldehyde, the oxime isformed and reduced to the hydroxylamine (XVI) as described empiricallybelow: ##STR32##

Preferably, the allylic substituent is oxidized to the aldehyde with aselective oxidant (to avoid oxidation to the carboxylic acid) (e.g.,ozone at low temperature). Preferably the aldehyde is converted to thecorresponding oxime by reaction with a hydroxylamine, preferablyO-substituted (e.g., O-benzylhydroxyamine), using mild acid or basecatalysis. The O-substitution facilitates the ring closure describedbelow. The oxime is reduced under mild conditions to avoid reduction tothe amine (e.g., sodium cyanoborohydride with acidic catalysis).

The hydroxylamine derivative (XVI) is then cyclized (condensed) to yieldthe 5 membered lactam (XVII). Alternatively, the benzyl ester, benzyl6-fluoro-2-methyl2,3-dihydro-4H)-benzopyran-4-carboxylate, could havebeen utilized in place of the methyl ester. This results in twodiastereomeric 5 membered lactam compounds which may be separated:##STR33##

Preferably, the lactam is reacted with a strong base such as asterically hindered amide ion (e.g., lithium diisopropylamide) attemperatures below about 0° C. Typically an aprotic solvent such as THFis used. Then the solution is acidified and the product isolated.

In those cases where the protecting group is used it is removed at thispoint for example, for the case of the O-benzyl ether (XVII), byhydrogenolysis to yield the desired end product N-hdyroxylactam (XVIII)functionality as described empirically below: ##STR34##

Preferably the protecting group is removed under conditions where theproduct hydroxy lactam is stable. For example, the O-benzyl protectinggroup is cleaved with hydrogen in the presence of a suitable noble metalsupported catalyst.

In general for the formation of compounds of formula I in which Y is##STR35## (the N-hydroxyimide functionality) the following reactionsequence is typically utilized. The appropriately substituted2,3-dihydro-4H-benzopyran-4-carboxylate (II) (i.e., substituted toachieve the desired W, X and R₂ functionality) is alkylated andhydrolyzed to the corresponding diacid (XIX) as described empiricallybelow: ##STR36##

Preferably the carboxylate is dissolved in a polar aprotic solvent suchas anhydrous N,N-dimethyl formamide and added to a base such as sodiumhydride. The reaction mixture is typically cooled to avoid uncontrolledexotherm and the appropriate alkyl haloacetate (e.g., to achieve thedesired R₁ ethyl bromoacetate) is added to yield the desired diester.The diester is hydrolyzed under basic conditions to yield the diacid.

The diacid (XIX) is then cyclized to the anhydride, which is reacted toform the hydroxamic acid-carboxylic acid which is dehydrated to form thedesired N-hydroxylimide (XX) functionality as described empiricallybelow ##STR37##

Preferably the diacid is dehydrated (e.g., reaction with aceticanhydride under reflux) to yield the anhydride. The anhydride is reactedwith hydroxylamine in an alcohol and ambient temperatures to yield thehydroxamic acid-carboxylic acid. The hydroxamic acid-carboxylic acid isthen dehydrated by for example heating in an inert solvent to form thedesired hydroxylimide.

The expression used herein, "pharmaceutically acceptable cationic salt",refers to non-toxic salts.

Thus, the compounds of this invention are acidic and they form basesalts. All such base salts are within the scope of this invention andthey can be prepared by conventional methods. For example, they can beprepared simply by contacting the acidic and basic entities, usually ina stoichiometric ratio, in either an aqueous, non-aqueous or partiallyaqueous medium, as appropriate. The salts are recovered either byfiltration, by precipitation with a non-solvent followed by filtration,by evaporation of the solvent, or, in the case of aqueous solutions, bylyophilization, as appropriate. For example the cation may be (but isnot limited to) sodium, potassium, calcium, magnesium, ammonium orprotonated benzathine (N,N'-dibenzylethylenediamine), choline,ethanolamine, diethanolamine, ethylenediamine, meglamine(N-methylglucamine), benethamine (N-benzylphenethylamine), piperazine ortromethamine (2-amino-2-hydroxymethyl-1,3-propanediol).

The compounds of this invention are all readily adapted to therapeuticuse as aldose reductase inhibitors for the control of chronic diabeticcomplications in mammals. They are administered either orally orparenterally, or topically as eye drops, in dosages ranging from about0.1 to 20 mg/kg of body weight per day in single or divided doses. Ofcourse, in particular situations, at the discretion of the attendingphysician, doses outside of this range will be used.

The compounds of this invention can be administered in a wide variety ofdifferent dosage forms, i.e., they may be combined with variouspharmaceutically-acceptable inert carriers in the form of tablets,capsules, lozenges, troches, hard candies, powders, sprays, elixirs,syrups, injectable or eye drop solutions, and the like. Such carriersinclude solid diluents or fillers, sterile aqueous media and variousnon-toxic organic solvents.

For purposes of oral administration, tablets containing variousexcipients such as sodium citrate, calcium carbonate and calciumphosphate are employed along with various disintegrants such as starchand preferably potato or tapioca starch, alginic acid and certaincomplex silicates, together with binding agents such aspolyvinylpyrrolidone, sucrose, gelatin and acacia Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often very useful for tabletting purposes. Solid compositionsof a similar type are also employed as fillers in soft and hard-filledgelatin capsules; preferred materials in this connection also includelactose or milk sugar as well as high molecular weight polyethyleneglycols. When aqueous suspensions and/or elixirs are desired for oraladministration, the essential active ingredient therein can be combinedwith various sweetening agents, flavoring agents, coloring agents,emulsifying agents and/or suspending agents, as well as such diluents aswater, ethanol, propylene glycol, glycerin and various like combinationsthereof.

For purposes of parenteral administration, solutions in sesame or peanutoil or in aqueous propylene glycol can be employed, as well as sterileaqueous solutions of the corresponding water-soluble, alkali metal oralkaline-earth metal salts previously enumerated. Such aqueous solutionsshould be suitably buffered, if necessary, and the liquid diluent firstrendered isotonic with sufficient saline or glucose. These particularaqueous solutions are especially suitable for intravenous,intramuscular, subcutaneous and intraperitoneal injection purposes. Inthis connection, the sterile aqueous media employed are all readilyobtainable by standard techniques well-known to those skilled in theart.

For purposes of topical administration, dilute, sterile, aqueoussolutions (usually in about 0.1% to 5% concentration), otherwise similarto the above parenteral solutions, are prepared in containers suitablefor dropwise administration to the eye, this being particularlyadvantageous for enhancing delivery to this organ.

In a pharmaceutical composition comprising a compound of formula I, or apharmaceutically-acceptable salt thereof, the weight ratio of carrier toactive ingredient will normally be in the range from 1:4 to 4:1, andpreferably 1:2 to 2:1. However, in any given case, the ratio chosen willdepend on such factors as the solubility of the active component, thedosage contemplated and the precise route of administration.

The compounds of this invention are useful for the control of diabeticcomplications. The activity can be determined by, for example, theconcentration that causes 50% inhibition of partially purified humanplacenta aldose reductase using glyceraldehyde as a substrate followingthe procedure described in U.S. Pat. No. 3,821,383 and based on theprocedure of Hayman et al., Journal of Biological Chemistry, 240, 877(1965). The substrate employed is partially purified aldose reductaseenzyme obtained from human placenta.

Activity can also be determined by, for example, the oral dose whichinhibits sorbitol accumulation in sciatic nerves of streptozotocizedrats by 50% by a procedure essentially as described in U.S. Pat. No.3,821,383. The amount of sorbitol accumulation in the sciatic nerves wasmeasured 27 hours after induction of diabetes. The compounds weregenerally administered orally at doses ranging from 2.5 to 100 mg/kg at4, 8 and 24 hours following the administration of streptozotocin. Theresults obtained compared to the case where no compound was administered(i.e., the untreated animal where sorbitol levels normally rise fromapproximately 50-100 mM/g tissue to as high as 400 mM/g tissue duringthe test period). Although, not all of the compounds of the presentinvention show in vivo activity by this oral test those compounds willfind parenteral or topical use.

EXAMPLE 1 1.6-fluoro-2,3-dihydro-4-cyano-4-[(trimethylsilyl)oxy]-4H-benzopyran

To a solution of 20 g (0.12 moles) of2,3-dihydro-6-fluoro-4H-benzopyran-4-one (prepared from 4-fluorophenoland acrylonitrile as described in J. Med. Chem., 28, 1716 (1985) and 23mL (0.18 moles) of trimethylsilyl cyanide in 220 mL of CH₂ Cl₂ was added500 mg of zinc iodide. The reaction was stirred at room temperature for20 hours then poured onto ice-water. The CH₂ Cl₂ layer was washed withwater, 10% aqueous NaHCO₃ and brine then dried over MgSO₄, filtered andevaporated to give 32 g of crude product which was used withoutpurification.

2. 6-fluoro-4-cyano-2H-benzopyran

To a solution of 32 g (0.12 mole) of the crude6-fluoro-2,3-dihydro-4-cyano-4-[(trimethylsilyl)oxy-]4H-benzopyran in170 ml of dry pyridine was added 60 ml (0.6 mole) of phosphorousoxychloride. The reaction was heated to reflux for 5 hours then cooledto room temperature. The resulting solution was added dropwise to asolution of 300 cc of concentrated HCl in 1 L of water. This aqueouslayer was extracted with EtOAc and the EtOAc layer was dried over Na₂SO₄, filtered and evaporated to give 16.1 g of product m.p. 114°-115° C.NMR (CDCl₃) ppm (delta) 5.00 (d, 2H, J=4 Hz), 6.6-7.3 (m, 4H).

3. 6-fluoro-2,3-dihydro-4-cyano-4H-benzopyran

To a solution of 16.1 g (0.092 moles) of 6-fluoro-4-cyano-2H-benzopyranin 270 mL of absolute methanol was added 5.52 g (0.23 mole) of magnesiumturnings. The resulting exothermic reaction was allowed to reflux thenstirred at room temperature for 2 hours. The volatiles were evaporatedand the residue dissolved in water which was acidified to pH 2.0 withconcentrated HCl. The aqueous was extracted with EtOAc and the EtOAclayer was dried over Na₂ SO₄, filtered and evaporated to give 16 g ofcrude product. The crude aproduct was purified by chromatography and 450g of silica gel eluting with CH₂ Cl₂ /ether to give 9 g of product m.p.67°-68° C. NMR CDCl₃ ppm (delta): 2.25 (dt, 2H, J=5 Hz), 4.95 (s, 1H,J=5 Hz), 4.00-4.30 (m, 2H), 6.70-7.05 (m, 3H). 4.6-fluoro-2,3-dihydro-4H-benzopyran-4-carboxylic acid

A solution of 8.5 g 0.05 moles) of6-fluoro-2,3-dihydro-4-cyano-4H-benzopyran and 21.8 g (0.39 moles) ofKOH in 250 ml of ethylene glycol was stirred and heated at 170° C.overnight.

The reaction was cooled and poured into water, acidified to pH 1 by theaddition of concentrated HCl and extracted with EtOAc. The EtOAc layerwas dried over Na₂ SO₄, filtered and evaporated to give 8.4 g of productm.p. 111°-115° C.

5. Methyl 6-fluoro-2,3-dihydro-4H-benzopyran-4-carboxylate

A solution of 8.4 g of the6-fluoro-2,3-dihydro-4H-benzopyran-4-carboxylic acid in 580 mL ofmethanol was perfused with HCl gas for 5 minutes. The resulting solutionwas stirred at room temperature overnight. The volatiles were evaporatedand the residue dissolved in ether. The ether layer was washed withwater then dried over Na₂ SO₄, filtered and evaporated to give 8.7 g ofcrude product which was purified by chromatography on 300 g of silicagel eluting with CH₂ Cl₂ to give 6.2 g of product as an oil. NMR (CDCl₃)ppm (delta): 2.00-2.40 (m, 2H), 3.80 (s, 3H), 2.5 (t, 1H, J=4 Hz),7.10-6.70 (m, 3H).

EXAMPLE 2 1. Methyl6-fluoro-3,4-dihydro-4-(hydroxymethyl)-2H-benzopyran-4-carboxylate

A solution of 5 mL (0.035 mole) of diisopropylamine in 100 mL of THF wascooled to 0° C. and 22.1 mL (0.35 mole) of 1.6M butyllithium in hexanewas added dropwise. After stirring for 30 minutes at 0° C. the resultingsolution was cooled to -78° C. A solution of 6.2 g (0.0295 mole) ofMethyl 6-fluoro-2,3-dihydro-4H-benzopyran-4-carboxylate in 20 mL of THFwas then added dropwise while maintaining the temperature below -66° C.The resulting solution was stirred at -78° C. for 3 hours. Gaseousformaldehyde was then bubbled into the solution for 5 minutes. Thereaction was allowed to warm to room temperature, then diluted withwater and extracted with EtOAc. The EtOAc layer was dried over Na₂ SO₄,filtered and evaporated to give 7.6 g of crude product as an oil. NMR(CDCl₃) ppm (delta): 2.20-2.60 (m, 2H), 3.8 (s, 3H), 4.26 (t, 2H, J=5Hz), 4.90 (m, 2H), 6.80-7.20 (m,3H).

    ______________________________________                                        Mass spectrum:                                                                              calc'd for C.sub.12 H.sub.13 O.sub.4 F                                                       240.0802                                                       found          240.0777                                         ______________________________________                                    

2. 6-fluoro-3,4-dihydro-4-(hydroxymethyl)-2H-benzopyran-4-carboxylicacid

To a solution of 7 g (0.029 mole) Methyl6-fluoro-3,4-dihydro-4-(hydroxymethyl)-2H-benzopyran-4-carboxylate in200 mL of McOH was added 7.2 mL of 5N NaOH. The reaction was heated on asteam bath overnight then cooled to room temperature. The MeOH wasevaporated and the residue dissolved in water then acidified to pH 4.0with concentrated HCl. The aqueous was extracted with EtOAc and theEtOAc layer was dried over Na₂ SO₄, filtered and evaporated to give 6 gof crude product. Chromatography on 160 g of silica gel eluting with CH₂Cl₂ /ether gave 2.7 g of product, m.p. 134°-135° C.

    ______________________________________                                        Mass spectrum:                                                                              calc'd for C.sub.11 H.sub.11 O.sub.4 F                                                       226.0642                                                       found          226.0646                                         ______________________________________                                    

3. 6-fluoro-3,4-dihydro-4-(hydroxymethyl)-2H-benzopyran-4-carboxylicacid

6-fluoro-3,4-dihydro-4-(hydroxymethyl)-2H-benzopyran-4-carboxylic acid1.99 g (0.0088 moles) was dissolved in 25 mL of H₂ O/DMF (4/1).O-Benzylhydroxylamine hydrochloride 2.8 g (0.0176 moles) was dissolvedin 60 mL of water and the pH of this solution was adjusted to 4.5 byaddition of 50% NaOH solution. This solution was then added dropwise tothe hydroxy acid solution. After adjusting the pH of the reactionmixture to pH 4.5, a solution of 3.36 g (0.0176 mole) of1-ethyl-3-(3-dimethylaminopropyl)carbodimide in 40 mL of H₂ O was addeddropwise while adjusting the pH of the reaction mixture to 4.5 byaddition of 1N HCl. The reaction was stirred at room temperature for 1hour then diluted with water and extracted with EtOAc. The EtOAc layerwas dried over Na₂ SO₄, filtered and evaporated to give 3.8 g crudeproduct. Chromatography on silica gel eluting with CH₂ Cl₂ /Et₂ O gave3.0 g of product. NMR (CDCl₃) ppm (delta): 2.00-2.40 (m, 2H), 3.60-4.35(m, 6H), 4.90 (s, 2H), 6.80-7.10 (m, 3H), 7.40 (s, 5H).

4.6-fluoro-3,4-dihydro-4-(methanesulfonyloxymethyl)-2H-benzopyran-4-N-(phenylmethoxy)-carboxamide

To a solution of 2.9 g (0.0088 moles) of6-fluoro-3,4-dihydro-4-(hydroxymethyl)-2H-benzopyran-4-N-(phenylmethoxy)-carboxamidein 60 mL of pyridine was cooled to 0° C. and 2 g (0.0176 moles) ofmethanesulfonylchloride was added dropwise. The reaction is allowed towarm to room temperature and stirred overnight. The reaction was pouredinto 400 mL of H₂ O/1NHCl (1/1). The resulting aqueous was thenextracted with EtOAc. The EtOAc extracts were dried over Na₂ SO₄,filtered and evaporated to give 3.7 g of crude product which was usedwithout purification.

5.6'-fluoro-2',3'-dihydro-4-phenylmethoxy-Spiro-[azetidine-3,4'-[4H-benzopyran]-2-one

To a suspension of 3.6 g (0.026 moles) of potassium carbonate in 100 mLof acetone was added 3.6 g (0.0088 moles) of6-fluoro-3,4-dihydro-4-(methanesulfonyloxymethyl)-2H-benzopyran-4-N-(phenylmethoxy)-carboxamide.The reaction was heated at reflux for 3 hours then cooled to roomtemperature and filtered. The filtrate was evaporated and the residuedissolved in EtOAc. The EtOAc layer was washed with H₂ O, dried over Na₂SO₄ and filtered to give 2.5 g of product, m.p. 60°-64° C.

    ______________________________________                                        Mass spectrum:                                                                             calc'd for C.sub.18 H.sub.16 NFO.sub.3                                                        313.1101                                                      found           313.1123                                         ______________________________________                                    

6.6'-fluoro-2',3',dihydro-1-hydroxy-spiro[azetidin-3,4'-[4H-benzopyran]-2-on

To a solution of 2.48 g (0.0079 moles) of the6'-fluoro-2',3'-dihydro-1-phenylmethoxy-spiro[azetidine-3,4'-[4H-benzopyran]-2-onein 150 ml of methanol was added 500 mg of 10% Pd of charcoal. Thereaction was stirred in a hydrogen atmosphere until N₂ uptake ceased.The reaction was filtered and the filtrate evaporated to give theproduct which was recrystallized from CH₂ Cl₂ to give 600 mg of product,m.p. 160°-161° C.

    ______________________________________                                        Mass spectrum:                                                                             calc'd for C.sub.11 H.sub.10 NO.sub.3 F                                                       223.0644                                                      found           223.0661                                         ______________________________________                                    

6',7'-dichloro-2',3'-dihydro-1-hydroxy-spiro-[azetidin-3,4'-benzopyran]-2-one(m.p. 157°-158° C.) was prepared in an analogous fashion to Example 2above, starting from benzyl 6,7-dichloro-4H-1-benzopyran-4-carboxylateby the same procedure as Example 2, via intermediacy of: benzyl4-(hydroxymethylene)-6,7-dichloro-4H-1-benzopyran-4-carboxylate (Rf=0.3(1:1 diethylether/hexanes, SiO₂),N-benzyloxy-4-(hydroxymethylene)-6,7-dichloro-4H-1-benzopyran-4-carboxamide(Rf=0.3 diethylether, SiO₂),N-benzyloxy-4-(methanesulfonoxymethylene)-6,7-dichloro-4H-1-benzopyran-4-carboxamide(Rf=0.3, 2:1 dichloromethane/ethyl acetate, SiO₂),1'-benzyloxy-2,3-dihydro-6,7-fluoro-spiro-(4H-1-benzopyran-4,3'-azetidine)-2'-one(Rf=0.7, 2:1 dichloromethane/ethyl acetate).

The less polar diastereomer of6'-fluoro-2',3'-dihydro-2'-methyl-1-hydroxy-spiro[azetidin-3,4'-benzopyran]-2-one(mp 173°-174°) and the more polar diastereomer of6'-fluoro-2',3'-dihydro-2'-methyl-1-hydroxy-spiro[azetidin-3,4'-benzopyran]-2-one (m.p. 118°-120° C.) were prepared in ananalogous fashion to Example 2 above from6-fluoro-2,3-dihydro-2-methyl-4H-benzopyran-4-one. The diastereomerswere separated by column chromatography on silica gel.

The less polar diastereomer of6'-fluoro-2',3'-dihydro-1-hydroxy-4-methyl-spiro[azetidin-3,4'-benzopyran]-2-one(m.p. 173°-174°) and the more polar diastereomer of6'-fluoro-2',3'-dihydro-1-hydroxy-4-methyl-spiro[azetidin-3,4'-benzopyran]-2-one(m.p. 178°-180° C.) were also made in analogous fashion to Example 2above, except acetaldehyde was used in place of formaldehyde in Part 1of Example 2. The

diastereomers were separated by column chromatography on silica gel.

EXAMPLE 36-fluoro-2,3-dihydro-spiro[4H-1-benzopyran-4,4'-isoxazolidin]-5'-one

In a 50 cc R.B. flask fitted with magnetic stirring was placed 30 cc ofabsolute ethanol, this was perfused with HCl gas for 10 minutes(saturated), this solution was allowed to cool to room temperature and120 mg of6'-fluoro-2',3'-dihydro-1-hydroxy-spiro-[azetidine-3,4'-[4H-benzopyran]-2-onein 3 cc of ethanol was added in one portion, the reaction was allowed tostir at room temperature for 60 minutes, then evaporated to a residuewhich was recrystallized from hexane/CH₂ Cl₂ to give 52 mg of product(m.p. 153°-155°).

EXAMPLE 4 1. Methyl6-Fluoro-3,4-dihydro-4-(methoxycarbonyl)-2H-benzopyran-4-butanoate

To a suspension of 8.81 g (0.183 mol) 50% NaH in 300 ml of DMF wasadded, dropwise, a solution of 27.5 g (0.131 mol) of methyl6-fluoro-2,3-dihydro-4H-benzopyran-4-carboxylate in 100 ml of DMF. Afterstirring at room temperature for 1 hour, a solution of 33 g (0.183 mol)of methyl 4-bromobutyrate in 25 ml of DMF was added. The resultanthomogeneous solution was stirred at room temperature for 16 hours andthen poured onto ice/H₂ O and acidified to pH 3.0 with concentrated HCl.The aqueous was extracted twice with CH₂ Cl₂ and the combined extractswere dried (NaSO₄) and filtered. The filtrate was evaporated in vacuo toan oil (44 g) which was purified by column chromatography on 2 Kg ofsilica gel, eluting with CH₂ Cl₂ /Et₂ O. Yield 12 g (30%), an oil; NMR(CDCl₃) (delta) 1.5-2 6(m, 8H, CH₂), 3.62 (s, 3H, CH₃), 3.66 (s, 3H,CH₃), 4.21 (t, 2H, J=6 Hz, CH₂), 6.7-7.4 (m, 3H, arom).

    ______________________________________                                        Mass spectrum:                                                                              calc'd for C.sub.16 H.sub.19 O.sub.5 F                                                       310.1216                                                       found          310.1184                                         ______________________________________                                    

2. Methyl6-fluoro-2,3-dihydro-2'-oxo-spiro[4H-benzopyran-4,1'-cyclopentane]-3'-carboxylate

To a suspension of 4.02 g (0.084 mol) of 50% NaH in 200 ml of DMF wasadded dropwise a solution of 11.8 g (0.089 mol) of methyl6-fluoro-3,4-dihydro-4-(methoxycarbonyl)-2H-benzopyran-4-butanoate. Theresultant homogeneous solution was stirred at room temperature for 16hours and then poured onto ice/H₂ O and acidified to pH 3.0 withconcentrated HCl. The aqueous was extracted twice with EtOAc and thecombined extracts were dried (NaSO₄) and filtered. The filtrate wasevaporated in vacuo to a solid residue (10.6 g, 100%), which wasrecrystallized from CH₂ Cl₂ /hexane m.p. 80°-83° C. The compound gave apositive FeCl test. NMR (CDCl₃) (delta) 1.6-2.8 (m, 6H, CH₂), 3.8 (s,3H, CH₃), 4.0-5.5 (m, 2H, CH₂), 6.6-6.9 (m, 3H, arom), 10.4 (s, 1H, OH).

    ______________________________________                                        Mass spectrum:                                                                              calc'd for C.sub.15 H.sub.15 O.sub.4 F                                                       278.0955                                                       found          278.0955                                         ______________________________________                                    

3. 6-fluoro-2,3-dihydro-2'-oxo-spiro[4H-benzopyran-4,1'-cyclopentane]

A mixture of 10.6 g (0.038 mol) of Methyl6-fluoro-2,3-dihydro-2'-oxo-Spiro[4H-benzopyran-4,1'-cyclopentane]-3'-carboxylatein 280 ml of 1N HCl containing 8 ml of concentrated HCl was heated atreflux for 3 hours. The reaction was cooled to room temperature andextracted twice with EtOAc. The combined extracts were dried over NaSO₄and filtered. The filtrate was evaporated in vacuo to a solid residue(5.7 g, 68%) which was recrystallized from petroleum ether: m.p. 49°-51°C. NMR (CDCl₃) (delta) 1.7-2.7 (m, 8H, CH₂), 4.0-4.5 (m, 2H, CH₂),6.4-6.9 (m, 3H, arom).

4.6-fluoro-2,3-dihydro-spiro[4H-benzopyran-4,1'-cyclopenten]-2',3'-dione,3'-oxime

A solution of 8.6 g (0.039 mol) of6-fluoro-2,3-dihydro-2'-oxo-Spiro[4H-benzopyran-4,1'-cyclopentane] and5.5 g (0.047 mol) of isoamyl nitrate in 200 ml of THF was cooled to 0°C. A suspension of 5.25 g of potassium t-butoxide in 50 ml of THF wasthen added portionwise keeping the temperature below 5° C. The reactionwas stirred at 0° for 5 minutes then poured into water and acidified topH 3.5 with HOAc. The aqueous was extracted twice with EtOAc and thecombined extracts were dried (NaSO₄) and filtered. The filtrate wasevaporated in vacuo to a solid residue (6.2 g, 64%) which wasrecrystallized from CH₂ Cl₂ /hexane: m.p. 170°-172° C.; NMR (CDCl₃)(delta) 1.8-3.2 (m, 6H, CH₂), 4.0-4.3 (m, 2H, CH₂), 6.5-6.9 (m, 3H,arom).

    ______________________________________                                        Mass spectrum:                                                                             calc'd for C.sub.13 H.sub.12 NO.sub.3 F                                                       249.0801                                                      found           249.0819                                         ______________________________________                                    

5.6-fluoro-2,3-dihydro-3'-hydroxy-spiro[4H-benzopyran-4,1'-[3]cyclopenten]-2'-one

A solution of 5.6 g (0.022 mol) of6-fluoro-2,3-dihydro-Spiro[4H-benzopyran-4,1'-cyclopenten]-2',3'-dione,3'-oxime in 50 ml of acetone and 50 ml of 1N HCl was heated at refluxfor 30 hours. The resultant solution was poured onto ice/H₂ O andextracted twice with EtOAc. The combined extracts were dried (NaSO₄) andfiltered. The filtrate was evaporated in vacuo to a solid residue whichwas recrystallized from CH₂ Cl₂ /hexane to give 2.6 g of product m.p.172°-173° C.; IR(KBr) 3350, 1695cm-1; NMR (acetone-d6) (delta) 1.8-2.2(m, 2H, CH₂), 3.8-4.6 (m, 2H, CH₂), 6.4-7.0 (m, 4H, arom and CH),7.8-8.6 (s, 1H, OH).

    ______________________________________                                        Mass spectrum:                                                                              calc'd for C.sub.13 H.sub.11 O.sub.3 F                                                       234.0692                                                       found          234.0699                                         ______________________________________                                    

The less polar diastereomer of6,7-dichloro-2,3-dihydro-2-methyl-3'-hydroxy-spiro[4H-benzopyran-4,1'-[3]cyclopenten]-2'-one(m.p. 158°-160°) and the more polar diastereomer of6,7-dichloro-2,3-dihydro-2-methyl-3'-hydroxy-spiro[4H-benzopyran-4,1'-[3]cyclopenten]-2'-one(m.p. 208°-210°) were prepared in an analogous fashion to Example 3 frommethyl 6,7-dichloro-2,3-dihydro-2-methyl-4H-benzopyran-4-carboxylate.The diastereomers were separated by column chromatography on silica gel.

The less polar diastereomer of6-fluoro-2,3-dihydro-2-methyl-3'-hydroxy-spiro[4H-benzopyran-4,1'-[3]cyclopent]-2'-one(m.p. 147°-148°) and the more polar diastereomer of6-fluoro-2,3-dihydro-2-methyl-3'-hydroxy-spiro[4H-benzopyran-4,1'-[3]cyclopent]-2'-one(m.p. 149°-150°) were prepared in an analogous fashion to Example 3 frommethyl 6-fluoro-2,3-dihydro-2-methyl-4H-benzopyran-4-carboxylate. Theenantiomers were separated by column chromatography on silica gel.

EXAMPLE 5 1. Methyl2,3-dihydro-6-fluoro-4-(2-propenyl)-4H-1-benzopyran-4-carboxylate

A solution of methyl 6-fluorochromane-4-carboxylate (2.1 g) in anhydrousN,N-dimethylformamide was added to a suspension of sodium hydride (265mg) in anhydrous N,N-dimethylformamide under nitrogen. After gasevolution ceased, the mixture was cooled to 0° C., and neat allylbromide (0.95 mL) was added. After 1 hour, 20 mL of an aqueous saturatedammonium chloride solution was added, and the mixture extracted withethyl acetate, the extracts washed with water, brine, dried overanhydrous sodium sulfate, filtered and evaporated to afford the titlecompound as a colorless oil, 2.4 g. (HRMS calc'd 250.1004; found250.1002).

2. Methyl2,3-dihydro-6-fluoro-4-(2-(benzyloxyamino)ethyl)4H-1-benzopyran-4-carboxylate

A solution of methyl2,3-dihydro-6-fluoro-4-(2-propenyl)-4H-1-benzopyran-4-carboxylate (3.8g) in 350 mL of a mixture of 10% saturated methanolic potassium hydrogencarbonate/90% dichloromethane was cooled to -78° C., and perfused with amixture of ozone in dry oxygen until a faint blue color persisted.Dimethyl sulfide (10 mL) was added, and the mixture was allowed to warmto room temperature. The mixture was evaporated under reduced pressure,partitioned between ethyl acetate and water, and the organic layersdried over anhydrous sodium sulfate, filtered, and evaporated. The oilyresidue was dissolved in anhydrous pyridine (75 mL), and solidO-benzylhydroxylamine was added and the mixture stirred at roomtemperature for 15 hours, then concentrated in vacuo. The residue wasdissolved in anhydrous methanol (150 mL), and solid sodiumcyanoborohydride (3.5 g) was added portionwise over 3 hours, alternatingwith additions of 1N aqueous HCl to maintain the mixture at pH 3-5.Solid sodium acetate was added, and the mixture concentrated in vacuo,extracted with ethyl acetate, and the organic extract washed with water,brine, dried over anhydrous sodium sulfate, filtered and evaporated. Theresidue was chromatographed over silica gel, eluting with diethylether/hexane (2:1) to yield the title compound, 3.1 g.

    ______________________________________                                        Mass spectrum:                                                                             calc'd for C.sub.20 H.sub.22 FNO.sub.4                                                        359.1533                                                      found           359.1539                                         ______________________________________                                    

3.1'-benzyloxy-2,3-dihydro-6-fluoro-spiro-(4H-1-benzopyran-4,3'-pyrrolidine)-2'-one

To a solution of methyl2,3-dihydro-6-fluoro-4-(2-(benzyloxyamino)ethyl)-4H-1-benzopyran-4-carboxylate(3.1 g) in anhydrous tetrahydrofuran at -78° C. was added a solution of1-M lithium diisopropylamide (9.0 mL) in tetrahydrofuran. After 1 houracetic acid (1 mL) was added, and the solution concentrated in vacuo.The residue was partitioned between ethyl acetate and 1N HCl, andorganic layers washed with 1N HCl, saturated aqueous sodium bicarbonate,brine, dried over sodium sulfate, filtered and evaporated to afford thetitle compound as an oil, 2.9 g. (¹ H NMR (CDCl₃, 60 MHz): 1.9-2.5 (m,4H), 3.2-4.6 (m, 4H), 5.0 (s, 2H), 6.3-6.8 (m, 3H), 7.3-7.5 (m, 5H).

4.1'-hydroxy-2,3-dihydro-6-fluoro-spiro-(4H-1-benzopyran-4,3'-pyrrolidine)-2'one

A solution of1'-benzyloxy-2,3-dihydro-6-fluoro-spiro-(4H-1-benzopyran-4,3'-pyrrolidine)-2'-one(1.4 g) in methanol (75 mL) containing 10% palladium on carbon (300 mg)was stirred vigorously under hydrogen gas (1 atm). After 18 hours, morepalladium on carbon (300 mg) was added, and the mixture was thenfiltered after being stirred under hydrogen gas for a further 20minutes. The filtrate was concentrated in vacuo, and the residuepurified by silica gel chromatography, eluting with ethyl acetate, toafford the title compound as a white crystalline solid, 780 mg, m.p.208°-209° C.

EXAMPLE 6 1. Benzyl(cis,trans)-2,3-dihydro-7-fluoro-2-methyl-4-(2-propenyl)-4H-1-benzopyran-4-carboxylate

To a suspension of sodium hydride (600 mg) in dimethylformamide (45 mL)was added benzyl-7-fluoro-2-methylchromane-4-carboxylate (6.0 g) indimethylformamide (30 mL). After evolution of hydrogen ceased, allylbromide (2.1 mL) was added in one portion, and the mixture stirred atroom temperature for 1 hour, then poured into ice/H₂ O (150 mL)/1N HCl(20 mL), extracted with ethyl acetate (3×100 mL) and the combinedorganic extracts washed with H₂ O, brine, dried over Na₂ SO₄, filteredand evaporated to yield the title compounds as an oil (6.9 gm, 1:1mixture of cis/trans). (Rf=0.6, 2.1 hexane/diethyl ether, SiO₂)

2 Benzyl (cis,trans)-2,3-dihydro-7-fluoro-2-methyl-4-(2-benzyloxyaminoethyl)-4H-1-benzopyran-4-carboxylate

A solution of benzyl(cis,trans)-2,3-dihydro-7-fluoro-2-methyl-4-(2-propenyl)-4H-1-benzopyran-4-carboxylatein dichloromethane (550 mL) and saturated methanolic potassiumbicarbonate (150 mL) cooled to -78° C. was perfused with a mixture ofozone in oxygen until the blue color of ozone persisted and consumptionof the starting olefin was complete as judged by thin layerchromatography (2:1 ethyl acetate/hexane on SiO₂) After purging withnitrogen, dimethyl sulfide (20 mL) was added, and the mixture allowed towarm to room temperature. After 2 hours, the mixture was concentratedunder reduced pressure and the residue partitioned between diethyl ether(200 mL) and water. The organic layer was washed repeatedly with water,brine, dried over Na₂ SO₄, filtered and concentrated under reducedpressure. The oily residue was dissolved in pyridine (100 mL), and solidO-benzylhydroxylamine hydrochloride (3.4 gm) added, and the mixturestirred at room temperature for 2 hours, then concentrated under reducedpressure. The residue was dissolved in ethyl acetate (200 mL) and washedwith saturated NaHCO₃, brine, dried (Na₂ SO₄), filtered and evaporated.The oily residue was then dissolved in tetrahydrofuran (150 mL)/H₂ O (10mL) and sodium cyanoborohydride (1.8 gm) added, followed by 1N aqueousHCl (30 mL). After 1 hour, additional sodium cyanoborohydride (1.8 gm)and 1N aqueous HCl (30 mL) were added, and the additions repeated againafter an additional 1 hour. After 2.5 hours total reaction time, solidsodium acetate (10 g) was added and the mixture concentrated underreduced pressure. The residue was diluted with H₂ O (100 mL) saturatedsodium bicarbonate (50 mL) and repeatedly extracted with ethyl acetate(3×150 mL). The combined organic extracts were washed with H₂ O, brine,dried (Na₂ SO₄), filtered and evaporated to yield an oily residue (9.2g), which was purified by column chromatography (diethyl ether/hexane2:1 over SiO₂) to yield the title compounds (6.0 g) (Rf=0.1, 2:1hexane/diethyl ether, SiO₂).

3. Cis and trans1'benzyloxy-2,3-dihydro-6-fluoro-2-methyl-spiro-(4H-1-benzopyran-4,3'-pyrrolidine)-2'-ones

To a solution of benzyl (cis,trans)-2,3-dihydro-7-fluoro-2-methyl-4-(2-benzyloxyaminoethyl)-4H-1-benzopyran-4-carboxylate(6.0 g) in anhydrous tetrahydrofuran (150 mL) at -78° C. was added asolution of 1N lithium diisopropylamide (16.3 mL) in tetrahydrofuran.After 1 hour acetic acid (4 mL) was added, and the solution concentratedin vacuo. The residue was partitioned between ethyl acetate and 1N HCl,and the organic layers washed with water, brine, dried over sodiumsulfate, filtered and evaporated to afford a crystalline solid, 5.2 g.

Crystallization from ethyl acetate/hexane gave a pure sample (1.1 g) ofthe chromatographically (diethyl ether/hexanes 2:1, SiO₂) more polardiastereomer. The mother liquors were concentrated under reducedpressure, and the residue purified by column chromatography (diethylether/hexanes 2:1, SiO₂) to afford a less polar diastereomer (1.75 g,m.p. 94°-95° C. from ethyl acetate/hexane) and an additional sample ofthe more polar diastereomer (700 mg, m.p. 143°-144° C. from ethylacetate/hexane).

4. More polar diasteromer of1'-hydroxy-2,3-dihydro-6-fluoro-2-methyl-spiro-(4H-1-benzopyran-4,3'-pyrrolidine)-2'one

A solution of the more polar diastereomer of1'-benzyloxy-2,3-dihydro-6-fluoro-2-methyl-spiro-(4H-1-benzopyran-4,3'-pyrrolidine)-2'-one(1.7 g) in methanol (75 mL) containing 10% palladium on carbon (350 mg)was stirred vigorously under hydrogen gas (1 atm). After 15 minutes, themixture was filtered, and the filtrate was concentrated in vacuo. Thetitle compound was obtained as needles following recrystallization fromethyl acetate hexanes (m.p. 205°-207° C., 840 mg).

5. The less polar diastereomer of1'-hydroxy-2,3-dihydro-6-fluoro-2-methyl-spiro-(4H-1-benzopyran-4,3'-pyrrolidine)-2'one

Prepared from the less polar diastereomer of1'-benzyloxy-2,3-dihydro-6-fluoro-2-methyl-spiro-(4H-1-benzopyran-4,3'-pyrrolidine)-2'-one(700 mg) by the same procedures used for the preparation of the productof Example 6, part 4 from the more polar diastereomer of1'-benzyloxy-2,3-dihydro-6-fluoro-2-methyl-spiro-(4H-1-benzopyran-4,3'-pyrrolidine)-2'-one,providing two apparent polymorphic crystalline forms, one (m.p. 132° C.,360 mg) obtained by crystallization of the crude product from ethylacetate hexanes and a second by crystallization (ethyl acetate/hexanes)of material obtained by column chromatography of the mother liquors(m.p. 189°-190° C., 330 mg).

EXAMPLE 7 1.2,3-dihydro-6-fluoro-2-(2-phenylethyl)-4H-1-benzopyran-4-one

Pyrrolidine (2.4 mL) was added to a solution of2'-hydroxy-5'-fluoroacetophenone (15.1 g) and 3-phenylpropanal (13.2 mL)in toluene (30 mL), and the mixture heated under reflux in a Dean-Starkapparatus for 3 hours, cooled, diluted with ethyl acetate and washedwith aqueous 1N HCl, aqueous 1N NaOH, H₂ O, brine, dried (Na₂ SO₄),filtered and evaporated, and the residue purified by columnchromatography (6:1 hexane/diethyl ether, SiO₂) to yield2,3-dihydro-6-fluoro-2-(2-phenylethyl)-4H-1-benzopyran-4-one (18 gm,Rf=0.3 4:1 hexane/diethyl ether).

2. Cis and trans4-cyano-2,3-dihydro-6-fluoro-2-(2-phenylethyl)-4H-1-benzopyran

2,3-dihydro-6-fluoro-2-(2-phenylethyl)-4H-1-benzopyran-4-one (8.9 gm)was dissolved in anhydrous tetrahydrofuran, andtoluenesulfonylmethylisocyanide (12.9 gm) added, followed by freshlyprepared sodium ethoxide in ethanol (prepared from sodium (1.5 gm) inethanol (60 mL) and the mixture stirred at room temperature overnight.The mixture was then concentrated in vacuo, and the residue partitionedbetween ethyl acetate and H₂ O, and the organic layer washed with H₂ O,brine, dried, filtered and evaporated. The residue was purified bycolumn chromatography (2:1 hexanes/diethyl ether) to yield4-cyano-2,3-dihydro-6-fluoro-2-(2-phenylethyl)-4H-1-benzopyran (2.7 gm,ir: 2250 cm⁻¹).

3. Cis and trans2,3-dihydro-6-fluoro-2-(2-phenylethyl)-4H-1-benzopyran-4-carboxylic acid

2,3-dihydro-6-fluoro-4-cyano-2-(2-phenylethyl)-4H-1-benzopyran (2.7 gm)and solid KOH (2.7 gm) were suspended in ethylene glycol (100 mL) andheated under reflux for 1.5 hours, then poured onto ice/H₂ O (300 mL),and extracted with diethyl ether, and the organic extracts discarded.The aqueous layer was acidified to pH 1 with 6N HCl, and extracted withethyl acetate, and the extracts washed with H₂ O, brine, dried, filteredand evaporated to yield the title compound (2.9 gm, m.p. 105°-108° C.).

4. Cis and trans methyl2,3-dihydro-6-fluoro-2-(2-phenylethyl)-4H-1-benzopyran-4-carboxylate

Cis and trans2,3-dihydro-6-fluoro-2-(2-phenylethyl)-4H-1-benzopyran-4-carboxylic acid(2.9 gm) was dissolved in methanol, cooled to 0° C., and the mixturesaturated with gaseous HCl. After 24 hours, the mixture was concentratedin vacuo, and the residue partitioned between ethyl acetate andsaturated sodium bicarbonate. The organic layer was washed with brine,dried (Na₂ SO₄), filtered and evaporated. The residue was purified bycolumn chromatography (2:1 hexane/diethyl ether, SiO₂) to yield thetitle compound (1.9 gm, Rf=0.3,2:1 hexane/diethyl ether, SiO₂).

5. More polar diasteromer of1-hydroxy-2,3-dihydro-6-fluoro-2-(2-phenylethyl)-spiro-(4H-1-benzopyran-4,3'-pyrrolidine)-2'one(m.p. 82°-84° C.)

Prepared from methyl2,3-dihydro-6-fluoro-2-(2-phenylethyl)-4H-1-benzopyran-4-carboxylate bythe same procedures used for the preparation of the product in Example6, part 4 from methyl2,3-dihydro-6-fluoro-4H-1-benzopyran-4-carboxylate, via intermediacy ofthe more polar diastereomer of1'-benzyloxy-2,3-dihydro-6-fluoro-2-(2-phenylethyl)-spiro-(4H-1-benzopyran-4,3'-pyrrolidine)-2'-one(Rf=0.2, 1:1 diethyl ether/hexanes).

EXAMPLE 8 1. 2,3-dihydro-6-fluoro-2-propyl-4H-1-benzopyran-4-one

2'-hydroxy-5'-fluoroacetophenone (2 gm) in tetrahydrofuran (10 mL) wasadded dropwise to sodium hydride (600 mg), then ethyl butyrate (10 mL)was added. After 30 minutes, aqueous 1N HCl (50 mL) was added, and themixture extracted with ethyl acetate, and the extracts washed with H₂ O,saturated aqueous NaHCO₃, brine, dried (Na₂ SO₄), filtered andevaporated. The residue was dissolved in dichloromethane (100 mL), andtrifluoroacetic acid (7 mL) added, and after stirring overnight at roomtemperature, dichloromethane and saturated aqueous NaHCO₃ were added,and the layers separated. The organic layer was washed with H₂ O, brine,dried (Na₂ SO₄), filtered and concentrated in vacuo to yield6-fluoro-2-propyl-4H-1-benzopyran-4-one (2.4 gm, Rf=0.4 1:1 diethylether/hexanes). This compound (9 gm) was dissolved in ethanol (250 mL)and sodium borohydride (1.6 gm) added, and the mixture heated underreflux. After 3.5 hours additional sodium borohydride (1.6 gm) added,and after 7 hours a further addition of sodium borohydride (1.6 gm) wasmade. After 10 hours more sodium borohydride (0.8 gm) was added andafter 23 hours total reaction time the mixture was concentrated underreduced pressure, and partitioned between ethyl acetate and H₂ O. Theorganic layer was washed with brine, dried (Na₂ SO₄), filtered andevaporated to yield4-hydroxy-2,3-dihydro-6-fluoro-2-propyl-4H-1-benzopyran-4-one (Rf=0.41:1 diethyl ether/hexanes). This material (10.8 gm) was dissolved inacetic acid (45 mL) and a solution of chromium trioxide (7.8 gm) inacetic acid (45 mL)/H₂ O (10 mL) was added dropwise. After one hour, themixture was poured into ice/H₂ O (1L) and extracted with ethyl acetate.The extracts were washed with H₂ O, saturated NaHCO₃, dried (Na₂ SO₄),filtered and evaporated to yield the title compound (7.4 g, Rf=0.7, 1:1diethyl ether/hexanes).

2. More polar diastereomer of1'-hydroxy-2,3-dihydro-6-fluoro-2-(2-propyl)-spiro-(4H-1-benzopyran-4,3'-pyrrolidine)-2'one(m.p. 138°-140° C.)

Prepared from 2,3-dihydro-6-fluoro-2-propyl-4H-1-benzopyran-4-one viathe intermediacy of the more polar diastereomer of1'-benzyloxy-2,3-dihydro-6-fluoro-2-(2-propyl)-spiro-(4H-1-benzopyran-4,3'-pyrrolidine)-2'one(Rf=0.2, 1:1 diethyl ether/hexanes) using the same procedure forpreparation of Example 7 from2,3-dihydro-6-fluoro-2-(2-phenylethyl-4H-1-benzopyran-4-one.

3. Less polar diastereomer of1'-hydroxy-2,3-dihydro-6-fluoro-2-(2-propyl)-spiro-(4H-1-benzopyran-4,3'-pyrrolidine)-2'-one(m.p. 109°-111° C.)

Prepared from 2,3-dihydro-6-fluoro-2-propyl-4H-1-benzopyran-4-one viathe intermediacy of the less polar diasteromer of1'-benzyloxy-2,3-dihydro-6-fluoro-2-(2-propyl)-spiro-(4H-1-benzopyran-4,3'-pyrrolidine)-2'one (Rf=0.3, 1:1 diethyl ether/hexanes) using the sameprocedure as that used for preparation of Example 7 from2,3-dihydro-6-fluoro-2-(2-phenylethyl)-4H-1-benzopyran-4-one.

EXAMPLE 9 1. Cis and trans6,7-dichloro-2,3-dihydro-2-methyl-4H-1-benzopyran-4-carboxylic acid

A mixture of 6,7-dichloro-2-methyl-4H-1-benzopyran-4-one (5 gm),cyanotrimethylsilane (3.5 mL), zinc iodide (670 mg) in dichloromethane(50 mL) was stirred at room temperature for 16 hours, then diluted withdichloromethane (200 mL), washed with saturated sodium bisulfite,saturated sodium bicarbonate, brine, dried (Na₂ SO₄), filtered andconcentrated in vacuo. The residue was added to concentrated H₂ SO₄ (30mL) in one portion at room temperature, and after 10 minutes, pouredonto ice/H₂ O, extracted with ethyl acetate and the organic layer washedwith H₂ O, brine, dried (MgSO₄), filtered and concentrated under reducedpressure. The residue was then dissolved in ethanol (50 mL), and sodiumborohydride (380 mg) added. After 15 minutes, the mixture wasconcentrated in vacuo, and the residue partitioned between ethyl acetateand H₂ O. The organic extracts were washed with H₂ O, brine, dried overNa₂ SO₄, filtered, and evaporated. The residue was then suspended inethylene glycol (100 mL), and solid KOH (5.4 gm) added. After heatingunder reflux for 2.5 hours, the mixture was cooled, and diluted with H₂O (300 mL), extracted with dichloromethane, and the organic extractback-washed with aqueous 1N KOH. The combined aqueous layers wereacidified with concentrated HCl to pH 1, extracted with ethyl acetate,and the organic extracts washed with water, brine, dried (MgSO₄),filtered and concentrated in vacuo. The residue was dissolved indichloromethane and decolorized with activated charcoal, filtered,concentrated vacuo, and crystallized from hexanes to yield the titlecompound (1.2 gm, m.p. 108°-110° C.).

2. Methyl cis and trans6,7-dichloro-2,3-dihydro-2-methyl-4H-1-benzopyran-4-carboxylate

cis and trans6,7-dichloro-2,3-dihydro-2-methyl-4H-1-benzopyran-4-carboxylic acid(27.4 gm) was dissolved in methanol (500 mL), cooled to 0° C., and thesolution saturated with gaseous HCl, then allowed to warm to roomtemperature. After 16 hours, the mixture was concentrated under reducedpressure, and the residue dissolved in ethyl acetate, washed withsaturated sodium bicarbonate, brine, dried (MgSO₄), filtered andevaporated. The residue was vacuum distilled (Kugelrohr, 150° C./1.5 mmHg) to yield the title compound (20 g, Rf=0.5, 1.1 diethylether/hexanes, SiO₂).

3. More polar diastereomer of1'-hydroxy-2,3-dihydro-6,7-dichloro-2-methylspiro-(4H-1-benzopyran-4,3'-pyrrolidine)-2'one(m.p. 118°-121° C.)

Prepared from methyl cis and trans6,7-dichloro-2,3-dihydro-2-methyl-4H-1-benzopyran-4-carboxylate in thesame manner as the product of Example 6, part 4 from more polardiastereomer of1'-benzyloxy-2,3-dihydro-6-fluoro-2-methyl-spiro-(4H-1-benzopyran-4,3'-pyrrolidine)-2'-one,via intermediacy of methyl cis and trans6,7-dichloro-2,3-dihydro-2-methyl-4-(2-propenyl)-4H-1-benzopyran-4carboxylate(Rf=0.6, 1:1 diethyl ether/hexanes, SiO₂), methyl cis and trans6,7-dichloro-2,3-dihydro-2-methyl-4-(2-benzyloxyaminoethyl)-4H-1-benzopyran-4-carboxylate(Rf=0.4, 1:1 diethyl ether/hexanes, SiO₂), and the more polardiasteromer of1'-benzyloxy-2,3-dihydro-6,7-dichloro-2-methyl-spiro-(4H-1-benzopyran-4,3'-pyrrolidine)-2'one(Rf=0.7, diethyl ether, SiO₂).

4. Less polar diastereomer of1'-hydroxy-2,3-dihydro-6,7-dichloro-2-methylspiro-(4H-1-benzopyran-4,3'-pyrrolidine)-2'one(m.p. 82°-85° C.)

Prepared in the same manner as Example 9, part 3 via intermediacy of theless polar diastereomer of1'-benzyloxy-2,3-dihydro-6,7-dichloro-2-methyl-spiro(4H-1-benzopyran-4,3'-pyrrolidine)-2'one(Rf=0.8, diethyl ether, SiO₂).

EXAMPLE 10 1.4-carboxymethylene-2,3-dihydro-6-fluoro-4H-1-benzopyran-4-carboxylicacid

A solution of methyl 6-fluorochromane-4-carboxylate (600 mg) inanhydrous N,N-dimethylformamide was added to a suspension of sodiumhydride (80 mg) in anhydrous N,N-dimethylformamide under nitrogen. Aftergas evolution ceased, the mixture was cooled to 0° C., and neat ethylbromoacetate (0.4 mL) was added. After 1 hour, aqueous 1N HCl (50 mL)was added, and the mixture extracted with ethyl acetate, the extractswashed with water, brine, dried over anhydrous sodium sulfate, filteredand evaporated. The residue was dissolved in ethylene glycol (50 mL) andafter addition of solid KOH (0.6 g), heated under reflux for 2.5 hours,then cooled, diluted with H₂ O (100 ml) extracted with ethyl acetate,and the organic layer discarded after washing with aqueous 5N KOH. Thecombined aqueous layers were acidified with concentrated HCl to pH 1 andextracted repeatedly with ethyl acetate. The combined extracts werewashed with water, brine, dried (Na₂ SO₄), filtered and concentratedunder reduced pressure. Crystallization of the residue from ethylacetate hexanes afforded the title compound (m.p. 211°-212° C., 150 mg).

2.1'-hydroxy-2,3-dihydro-6-fluoro-spiro-(4H-1-benzopyran-4,3'-pyrrolidine-2'one

The diacid (1.02 gm) was dissolved in acetic anhydride (50 mL) andheated under reflux for 3 hours. After concentration under reducedpressure, column chromatography (1:1 diethyl ether/hexane, SiO₂), theresulting anhydride was dissolved in methanol (5 mL) and a solution ofhydroxylamine in methanol, prepared from hydroxylamine hydrochloride(310 mg), sodium methoxide (240 mg) in methanol (10 mL), was added.After 3 hours, the mixture was concentrated in vacuo. The residue wasthen heated in xylenes under reflux for 3.5 hours, and after removal ofsolvent under reduced pressure, the residue was crystallized (ethylacetate/hexanes) to yield the title compound (m.p. 190°-192° C., 155mg).

EXAMPLE 11 1. Cis/trans-6-fluoro-4-methoxycarbonyl-2-methyl-1-tetralone

To a solution of methyl 3-fluorophenylacetate (prepared from 3fluorophenylacetic acid (Aldrich Chem. Co., Madison, Wis.) viaesterification with methanol catalyzed by gaseous HCl) in anhydrousN,N-dimethylformamide (40 mL) warmed to 70° C. was added methylmethacrylate (5.8 mL) and potassium tertbutoxide (0.55 gm). After 15minutes, aqueous 1N HCl (75 mL) was added, and the mixture extractedwith diethyl ether. The organic extracts were washed with H₂ O, brine,dried (Na₂ SO₄, filtered and evaporated. The residue was dissolved inconcentrated H₂ SO₄ (80 mL)/H₂ O (20 mL), and warmed to 70° C. for 3hours, then poured onto crushed ice, and the mixture extracted withethyl acetate. The extracts were washed with H₂ O, brine, dried (Na₂SO₄, filtered and evaporated. The oily residue was dissolved in methanol(250 mL), and the solution saturated with gaseous HCl. After 30 minutes,the mixture was purged with nitrogen, and concentrated under reducedpressure. The oily residue was partitioned between H₂ O (500 mL), andethyl acetate, and the organic layer washed with water, brine, dried(Na₂ SO₄), filtered and concentrated in vacuo to yield the titlecompound (10.9 gm, Rf (1:1 diethyl ether/SiO₂)=0.4).

2.Cis/trans-6-fluoro-4-methoxycarbonyl-2-methyl-4-(2-propenyl)-1-tetralone

A solution of cis/trans-6-fluoro-4-methoxycarbonyl-2-methyl-1-tetralone(3.6 g) in anhydrous N,N-dimethylformamide (20 mL) was added dropwise toa suspension of sodium hydride (400 mg) in anhydrousN,N-dimethylformamide (70 mL) and the mixture stirred at 0° C. for 15minutes. Neat allyl bromide (1.4 mL) was then added, and after 20minutes, aqueous 1N HCl (50 mL) was added, the mixture extracted withethyl acetate, and the organic layers washed with H₂ O, brine, dried(Na₂ SO₄) filtered and evaporated to afford the title compound (4.2 g,Rf (1:1 diethyl ether/SiO₂)=0.5).

3.Cis/trans-6-fluoro-4-methoxycarbonyl-2-methyl-4-(2-benzyloxyaminoethyl)-1-tetralone

Prepared fromcis/trans-6-fluoro-4-methoxycarbonyl-2-methyl-4-(2-propenyl)-1-tetraloneas per the procedure outlined for Example 6, part 4 above, (Rf (1:1diethyl ether/SiO₂)=0.3).

4. Cis and trans1'-benzyloxy-6-fluoro-2-methyl-spiro-(1-oxotetralin-4,3'-pyrrolidine)-2'ones

Prepared fromcis/trans-6-fluoro-4-methoxycarbonyl-2-methyl-4-(2-benzyloxyaminoethyl)-1-tetraloneas per the procedure outlined for Example 6, part 4 above. Theindividual diastereomers were isolated by column chromatography (3:1diethyl ether/hexanes, SiO₂) yielding a less polar diastereomer (m.p.128°-130° C.) and a more polar diastereomer (m.p. 110°-112° C.).

5.1'-hydroxy-6-fluoro-2-methyl-spiro-(1-oxotetralin-4,3'-pyrrolidine)-2'-one

A solution of the more polar diastereomer of cis and trans1'-benzyloxy-6-fluoro-2-methyl-spiro-(1-oxotetralin-4,3'-pyrrolidine)-2'-onein methanol (30 mL) containing 10% palladium on carbon (80 mg) wasstirred vigorously under hydrogen gas (1 atm). After 25 minutes themixture was filtered and the filtrate was concentrated in vacuo.Trituration with diethyl ether yielded the title compound as whitecrystalline solid, 137 mg, (m.p. 106°-108° C.).

EXAMPLE 12 1. 6,7-dichloro-4H-1-benzopyran-4-carboxylic acid

To a solution of 2-trimethylsilyl-1,3-dithiane in anhydroustetrahydrofuran (500 mL) at -78° C. under nitrogen was added 2.5Mn-butyllithium in hexane (64 mL), and the mixture then allowed to warmto 0° C. After 2 hours, the mixture was cooled to -78° C. and a solutionof 6,7-dichloro-4H-1-benzopyran-4-one in anhydrous tetrahydrofuran (150mL) added dropwise. The mixture was then allowed to warm to roomtemperature. After 16 hours, the solvent was removed under reducedpressure, and the residue partitioned between ethyl acetate and H₂ O,and organic extract washed with H₂ O, brine, dried (Na₂ SO₄), filteredand evaporated. The residue was dissolved in a mixture of acetic acid(750 mL), H₂ O (375 mL) and trifluoroacetic acid (15 mL) and heatedunder reflux for 20 hours, then cooled and poured into ice/H₂ O (2.5 L).The mixture was extracted with ethyl acetate and the organic extractswashed with water, saturated NaHCO₃, brine, dried (Na₂ SO₄), filteredand evaporated. The residue was suspended in ethanol (800 mL)/H₂ O (400mL), solid KOH (38 g) added, and the mixture heated under reflux for 1.5hours. After concentration under reduced pressure, the mixture wasdiluted with H₂ O (600 mL), extracted with diethyl ether, and the etherextracts discarded. The aqueous layer was acidified to pH 1 withconcentrated HCl, and extracted with ethyl acetate, and the extractswashed with water, brine, dried (Na₂ SO₄), filtered and evaporated.Trituration of the solid residue with boiling hexane yielded the titlecompound (16.8 gm, m.p. 114°-117° C.).

2. Benzyl 6,7-dichloro-4H-1-benzopyran-4-carboxylate

A mixture of 6,7-dichloro-4H-1-benzopyran-4-carboxylic acid (16.8 gm),tetra (N-butyl)ammonium hydrogensulfate (23 gm), benzyl bromide (9.7mL), saturated sodium bicarbonate (100 mL) and dichloromethane (100 mL)were stirred vigorously at room temperature for 14 hours, then dilutedwith dichloromethane, and the organic layer separated, washed withsaturated sodium bicarbonate, water, brine, dried (MgSO₄), filtered andevaporated. The residue was purified by column chromatography (2:1dichloromethane/hexanes, SiO₂) to afford the title compound (11.8 gm,Rf=0.3 (2:1 dichloromethane/hexanes, SiO₂).

It should be understood that the invention is not limited to theparticular embodiments shown and described herein, but that variouschanges and modifications may be made without departing from the spiritand scope of this novel concept as defined by the following claims.

What is claimed is:
 1. A compound of the formula ##STR38## wherein Y is##STR39## X is --O-- or ##STR40## R₁ and R₂ are each independently H,alkyl C₁ -C₆, aryl or arylalkyl (C₁ -C₆);W₁ and W₂ are eachindependently hydrogen, halogen or nitro; andthe pharmaceuticallyacceptable base addition salts thereof.
 2. A compound of claim 1 whereinX is ##STR41##
 3. A pharmaceutical composition for the control ofchronic diabetic complications in mammals which comprises an effectiveamount of a compound of claim 1 in a pharmaceutically acceptablecarrier.
 4. A method of controlling chronic diabetic complications whichcomprises administering to a mammal suffering from chronic diabetes achronic diabetic complication controlling amount of a compound ofclaim
 1. 5. A compound of claim 1 wherein X is --O--.
 6. A compound ofclaim 5 wherein W₁ and W₂ are each independently hydrogen or halogen andR₁ and R₂ are each independently H or alkyl(C₁ -C₆).
 7. A compound ofclaim 6 wherein R₁ is hydrogen or methyl, R₂ is hydrogen or methyl, andeither W₁ and W₂ are each chlorine in position 6 and 7 respectively orW₁ is hydrogen and W₂ is fluorine in position 6.